- Email: [email protected]
Gallstone disease in mestizo Hispanics
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ANDREW K. DIEHL
19. Jodal M, Lundgren O. Neural reflex modulation of intestinal epithelial transport. In: Gaginella TS, ed. Regulatory mechanisms in gastrointestinal function. Boca Raton, FL: CRC Press, 1995:99– 144. 20. Skok VI, Groisman SD, Melnitchenko LV, Gersanich VV, Gmiro VE. Selective pharmacological blockade of parasympathetic and enteric ganglia. J Auton Nerv Syst 1991;35:211–217. 21. Timar Peregrin A, Svensson M, Jodal M, Lundgren O. Calcium channels and intestinal fluid secretion: an experimental study in vivo in rats. Acta Physiol Scand 1997;160:371–378. 22. Timar Peregrin A, Ahlman H, Jodal M, Lundgren O. Effects of
GASTROENTEROLOGY Vol. 115, No. 4
calcium channel blockade on intestinal fluid secretion: sites of action. Acta Physiol Scand 1997;160:379–386. 23. Timar Peregrin A. Calcium channels, nerves and intestinal secretion (thesis). Go¨teborg University, 1998.
Address requests for reprints to: Ove Lundgren, M.D., Ph.D., Department of Physiology, Go ¨teborg University, Box 432, 405 30 Go ¨teborg, Sweden. e-mail:[email protected] r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
Gallstone Disease in Mestizo Hispanics See article on page 937.
allstone disease is remarkably common and is a major contributor to health care costs in the United States. Approximately one fourth of white women older than 50 are affected,1 and more than 700,000 cholecystectomies were performed in this country in 1995.2,3 The disease is not distributed equally across racial and ethnic groups. African Americans have rates half those of non-Hispanic whites. In contrast, Native Americans and certain American Hispanic populations are at high risk for gallstones and their complications.1 The extraordinary prevalence of gallstones in the Pima tribe of Arizona is well known. Almost 30 years ago, Sampliner et al.4 found that more than 70% of Pima women aged 25 and older had a history of cholecystectomy or abnormal cholecystographic findings. Subsequent investigators have reported high rates in other North American indigenous groups, including the Chippewas, Micmacs, and Cree-Ojibwas.5,6 Moreover, Native Americans living in Alaska, New Mexico, and Bolivia have high mortality from gallbladder cancer, a disease intimately linked to gallstones. That these high rates are observed in native peoples who differ markedly in local environment, culture, and diet argues for a common, genetically determined predisposition to stone formation.5 Certain Hispanic populations in the United States also appear to be at above average risk for gallbladder diseases. Preliminary data from the Third National Health and Nutrition Examination Survey document a higher prevalence of gallstones among Mexican Americans than non-Hispanic whites.7 This population-based epidemiological survey, which used real-time ultrasonography,
G
confirms earlier reports using less rigorous methods.5 Our own studies have found that the higher risk of clinically diagnosed gallstones in Mexican American women persists in analyses accounting for interethnic differences in age, body mass index, waist-to-hip ratio, parity, glucose intolerance, socioeconomic status, and dietary preferences.5,8,9 Mexican Americans have a correspondingly high mortality from gallbladder cancer compared with non-Hispanic whites.5,10 However, the risk is not uniform among U.S. Hispanic subgroups. The Hispanic Health and Nutrition Examination Survey (Hispanic HANES) found that Mexican Americans had an elevated risk for gallstone disease in comparison with Cuban Americans and mainland Puerto Ricans, even after adjustment for other relevant risk factors.11 Gallbladder cancer mortality in Mexican Americans is more than twice that of Cuban Americans and Puerto Ricans.10 Data on U.S. Hispanics of Central or South American origin are sparse but suggest rates of gallbladder disease only slightly less than those of Mexican Americans.10 Of note, gallstone prevalence in Spain is similar to that in other European countries.12 Why should gallstone disease be such a problem in some, but not other, Hispanic populations? The leading hypothesis is based on concepts of genetic admixture. Some U.S. Hispanic subgroups, most notably the Mexican Americans, are known to have a mestizo (mixed) genetic heritage. Modern Mexican Americans are the descendants of the Native Americans who originally populated Mexico and of the European conquistadores and immigrants who began arriving early in the sixteenth century. Recent investigations estimate that 30%–50% of the genetic stock of Mexican Americans derives from Native American sources.13 In contrast, Native American
October 1998
genes are believed to be less prevalent in Cuban Americans and Puerto Ricans, because of the rapid decimation of the indigenous populations of their islands of origin during the Spanish Conquest. If the admixture hypothesis is correct, one would expect to find a gradient in the prevalence of gallbladder disease, with mestizo Hispanics having a prevalence higher than that of non-Hispanic whites, but less than unadmixed Native Americans. There are several documented examples of such a gradient. In New Mexico, Morris et al.14 calculated mortality for noncancerous gallbladder disease for the mestizo Spanish American population. Using death certificate data, they found rates of 7.3 per 100,000 for Spanish American women vs. 2.7 for non-Hispanic whites and 16.6 for Native American women. For men, the corresponding rates were 4.1, 2.8, and 15.3 per 100,000. Rates of gallbladder cancer mortality in Spanish Americans similarly fell between those for Native Americans and non-Hispanic whites.14 In Bolivia, Rios-Dalenz et al.15 found mestizos to have a gallbladder cancer incidence higher than that of ‘‘whites’’ but less than that of Native Americans15; a more recent study from that country had similar findings.16 In this issue of GASTROENTEROLOGY, Miquel et al.17 provide additional data from Chile in support of the admixture hypothesis. Chileans have a very high prevalence of gallbladder disease, and Chile’s mortality rate from gallbladder cancer is among the highest in the world. In fact, gallbladder cancer has in recent years surpassed stomach, cervix, and breast cancer as the leading cause of cancer death in Chilean women.18 The factors underlying these high rates have yet to be elucidated. In an elegant epidemiological study, Miquel et al.17 reexamined the role genetic admixture plays in explaining variations in gallstone disease prevalence among ethnic subpopulations in Chile. Three groups were sampled. The largest was a middle-low socioeconomic group of mestizo Hispanics from an urban neighborhood in Santiago. The investigators also examined an isolated population of Mapuche Native Americans living on a small island in a lake in rural southern Chile. Finally, the investigators surveyed an entirely unrelated group of Chilean Maoris living on Easter Island in the Pacific Ocean. Subjects were asked about a history of cholecystectomy and underwent screening ultrasonography. In contrast to most previous studies, Native American genetic admixture was measured directly via ABO blood group distribution and determination of mitochondrial DNA polymorphisms.
EDITORIALS
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As expected, the prevalence of gallstones differed in the three populations, Mapuches having the highest rates and Maoris the lowest. Mapuches had significantly higher estimates of Amerindian genetic heritage than Hispanic mestizos, although a large majority of Hispanics were found to have some Amerindian genes. Maoris had no evidence of Amerindian admixture. Thus, the overall findings support the admixture hypothesis. However, subgroup data are not uniform or consistent. Only Mapuches aged 35 years and younger, especially women, had higher gallstone prevalences than mestizo Hispanics. There was no significant difference in prevalence between Mapuches and Hispanics of either sex after adjustment for age, body mass index, parity, and serum high-density lipoprotein cholesterol level. The prevalence of gallstones in Maoris was significantly lower than that of mestizo Hispanics only in persons older than 50 years. However, because the study had relatively low statistical power, true between-group differences may have gone undetected. In addition, the high degree of Amerindian admixture among the mestizo Hispanics may have limited the investigators’ ability to delineate differences in prevalence among age and sex subgroups. A few studies have attempted to relate the degree of Native American admixture to gallstone risk within a mestizo Hispanic population. A substudy of Mexican Americans from the Hispanic HANES found that Native American admixture (estimated by the highly polymorphic GM immunoglobulin antigen system) was unrelated to gallstone prevalence in either sex.19 Hanis et al.20 used a panel of blood group antigens and enzyme markers to characterize the degree of admixture in Mexican Americans. They found that among women younger than 45 years, greater levels of admixture were associated with a higher prevalence of clinical gallbladder disease. This relationship was not observed in men or older women.20 Mitchell et al.13 used three independent measures of admixture to characterize Mexican Americans participating in the San Antonio Heart Study. They found women with the highest admixture 1.4–1.8 times more likely to have clinically diagnosed gallbladder disease than those with the least admixture, although only one of the three ratios was statistically significant. No significant impact of admixture was observed in men.13 Together these findings provide meager support for the genetic admixture hypothesis, although differences within mestizo groups might be expected to be more difficult to show than those between mestizos and Native Americans. It is notable that, as observed in the study by Miquel et al., the most prominent effects of admixture were observed in younger women. One might conclude that in conditions
1014
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of multifactorial cause (like cholelithiasis), the impact of genetic factors is more evident in youth. Alternatively, genetic factors may interact with hormonal or other biological differences related to gender. Despite the uncertain implications of the admixture studies performed to date, it is clear that Native Americans and mestizo Hispanics have higher rates of gallbladder disease than non-Hispanic whites. Some have argued that the postulated genetic predisposition to cholethiasis in Native Americans is the consequence of evolutionary forces. According to this theory, the first persons to cross the Bering land bridge from Asia 10–20,000 years ago faced harsh environmental conditions, with unpredictable periods of nutritional and caloric insufficiency. Under these selection pressures, genes that promoted the efficient utilization and storage of nutrients by females might have become more prevalent. Such evolutionary drift of a ‘‘thrifty gene’’ might, eons later, result in the rapid formation of cholesterol gallstones under the conditions of nutritional plenty these populations are now experiencing.21,22 Stimulated by the discovery of the Lith1 gene in an inbred mouse model,23 investigators are now seeking a corresponding gene in humans. Currently, surprisingly little is known of the pathogenesis of gallstone formation in Native Americans and mestizo Hispanics. It has been established that Pimas rapidly develop lithogenic bile at puberty.24 However, Mexican Americans are no more likely to present with cholesterol or mixed composition stones than nonHispanic whites, and stones recovered at surgery from the two groups are remarkably similar in size and number.25 Future studies should examine other aspects of stone pathogenesis in Native American and admixed populations including gallbladder emptying, which has been found to differ between racial groups.26 Given the magnitude of gallbladder disease prevalence and the resources currently devoted to its treatment, our goal should be to develop a practical means to prevent stone formation. Insights will come from basic science as well as epidemiological studies. Further exploration of the mechanisms underlying the high prevalence of gallstone disease in Native Americans and mestizo Hispanics may be especially fruitful. ANDREW K. DIEHL Division of General Medicine Department of Medicine University of Texas Health Science Center San Antonio, Texas
References 1. Diehl AK. Epidemiology and natural history of gallstone disease. Gastroenterol Clin North Am 1991;20:1–19.
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2. Graves EJ, Owings MF. 1995 summary: National Hospital Discharge Survey. Advance data from vital and health statistics; no. 291. Hyattsville, MD: National Center for Health Statistics, 1997. 3. Hall MJ, Lawrence L. Ambulatory surgery in the United States, 1995. Advance data from vital and health statistics; no. 296. Hyattsville, MD: National Center for Health Statistics, 1997. 4. Sampliner RE, Bennett PH, Comess LJ, Rose FA, Burch TA. Gallbladder disease in Pima Indians. Demonstration of high prevalence and early onset by cholecystography. N Engl J Med 1970;283:1358–1364. 5. Diehl AK, Stern MP. Special health problems of MexicanAmericans: obesity, gallbladder disease, diabetes mellitus, and cardiovascular disease. Adv Intern Med 1989;34:73–96. 6. Young TK, Roche BA. Factors associated with clinical gallbladder disease in a Canadian Indian population. Clin Invest Med 1990; 13:55–59. 7. Khare M, Everhart JE, Maurer KR, Hill MC. Prevalence of gallstone disease in the United States (abstr). Hepatology 1994;20:118A. 8. Haffner SM, Diehl AK, Mitchell BD, Stern MP, Hazuda HP. Increased prevalence of clinical gallbladder disease in subjects with non–insulin-dependent diabetes mellitus. Am J Epidemiol 1990;132:327–335. 9. Diehl AK, Haffner SM, Knapp JA, Hazuda HP, Stern MP. Dietary intake and the prevalence of gallbladder disease in Mexican Americans. Gastroenterology 1989;97:1527–1533. 10. Wagener DK, McDonald M. Increased gallbladder-related mortality among Hispanics: does education play a role? Ethn Health 1996;1:197–205. 11. Maurer KR, Everhart JE, Knowler WC, Shawker TH, Roth HP. Risk factors for gallstone disease in the Hispanic population of the United States. Am J Epidemiol 1990;131:836–844. 12. Martinez de Pancorbo C, Carballo F, Horcajo P, Aldeguer M, Hazuda HP, Haffner SM, Stern MP. Prevalence and associated factors for gallstone disease: results of a population survey in Spain. J Clin Epidemiol 1997;50:1347–1355. 13. Mitchell BD, Williams-Blangero S, Chakraborty R, Valdez R, de la Villa I, Nieto E, Gaspar MJ, de la Moreno J. A comparison of three methods for assessing Amerindian admixture in Mexican Americans. Ethn Dis 1993;3:22–31. 14. Morris DL, Buechley RW, Key CR, Morgan MV. Gallbladder disease and gallbladder cancer among American Indians in tricultural New Mexico. Cancer 1978;42:2472–2477. 15. Rios-Dalenz J, Takabayashi A, Henson DE, Strom BL, Soloway RD. The epidemiology of cancer of the extra-hepatic biliary tract in Bolivia. Int J Epidemiol 1983;12:156–180. 16. Strom BL, Soloway RD, Rios-Dalenz J, Rodriguez-Martinez HA, West SL, Kinman JL, Polansky M, Berlin JA. Risk factors for gallbladder cancer. An international collaborative case-control study. Cancer 1995;76:1747–1756. 17. Miquel JF, Covarrubias C, Villaroel L, Mingrone G, Greco AV, Puglielli L, Carvallo P, Marshall G, Del Pino G, Nervi F. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris. Gastroenterology 1998;115:937– 946. 18. Serra I, Calvo A, Maturana M, Sharp A. Biliary-tract cancer in Chile. Int J Cancer 1990;46:965–971. 19. Everhart JE, Knowler WC, Maurer KR, Harris MI, Schanfield MS, Go VLW. Does American Indian admixture contribute to obesity, diabetes, and gallbladder disease among Mexican Americans? Am J Epidemiol 1989;130:840. 20. Hanis CL, Chakraborty R, Ferrell RE, Schull WJ. Individual admixture estimates: disease associations and individual risk of diabetes and gallbladder disease among Mexican-Americans in Starr County, Texas. Am J Phys Anthropol 1986;70:433–441. 21. Weiss KM, Ferrell RE, Hanis CL, Styne PN. Genetics and epidemiology of gallbladder disease in New World native peoples. Am J Hum Genet 1984;36:1259–1278.
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EDITORIALS
22. Lowenfels AB. Gallstones and glaciers: the stone that came in from the cold. Lancet 1988;1:1385–86. 23. Khanuja B, Cheah Y-C, Hunt M, Nishina PM, Wang DQ-H, Chen HW, Billheimer JT, Carey MC, Paigen B. Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc Natl Acad Sci 1995;92:7729–7733. 24. Bennion LJ, Knowler WC, Mott DM, Spagnola AM, Bennett PM. Development of lithogenic bile during puberty in Pima Indians. N Engl J Med 1979;300:873–876. 25. Diehl AK, Schwesinger WH, Holleman DR Jr, Chapman JB, Kurtin WE. Gallstone characteristics in Mexican Americans and nonHispanic whites. Dig Dis Sci 1994;39:2223–2228.
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26. Davion T, Tossou H, Delamarre J, Capron J-P. Racial differences in gallbladder motor function. Lancet 1989;1:724–725.
Address requests for reprints to: Andrew K. Diehl, M.D., Division of General Medicine, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7879. e-mail: [email protected]; fax: (210) 223-6166. r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
The Mechanisms of Chronicity in Hepatitis C Virus Infection See article on page 954.
he outcome of a viral infection is defined by the interplay between the virus and host immune response. Clearance of a virus is usually associated with a vigorous antiviral T-cell response. Because viruses are intracellular pathogens, CD8 cytotoxic T lymphocytes (CTLs) that can directly kill infected cells and produce potent antiviral cytokines are thought to be crucial in viral eradication and disease control. In contrast, persistent viruses are relatively noncytopathic viruses that successfully evade immune detection and elimination. Indeed, the latter are very sophisticated viruses that have developed various mechanisms to subvert or obfuscate the host immune system to survive. Hepatitis C virus (HCV) is particularly interesting in this context because of its high rate of chronicity (.70%).1 Since its identification and molecular characterization in 1989,2 this hepatotropic positive-stranded RNA virus has emerged as an important pathogen that infects more than 1% of the world population.3,4 Paradoxically, chronic hepatitis C occurs in the face of a readily detectable multispecific humoral and cellular immune response directed against all of the viral structural and nonstructural proteins.5–7 Because persistent HCV infection is usually associated with chronic hepatitis, which often progresses to cirrhosis, and may lead to hepatocellular carcinoma, considerable interest has been focused on potential mechanisms of viral persistence and immune evasion.8–11 In this editorial, potential mechanisms of HCV persistence, including the role of CTL escape, are discussed in the context of published literature and the current article by Tsai et al.12 in this issue of GASTROENTEROLOGY.
T
Proposed Mechanisms of Viral Immune Evasion The host defense mechanisms against viral pathogens include innate responses such as natural killer cells and interferons that are antigen-nonspecific and antigenspecific immune responses such as antibody, CD4, and CD8 T-cell response. In this context, viruses can persist by interfering with components of the immune response. They can compromise the immune system directly by infecting lymphocytes and antigen-presenting cells, as evident in human immunodeficiency virus (HIV) infection.13 They can avoid immune recognition by infecting immunologically privileged sites or by remaining latent, as shown by herpes simplex virus. Viruses such as adenoviruses, HIV, and herpesviruses have been shown to interfere with antigen processing,14 whereas Epstein– Barr virus, poxvirus, and others produce viral cytokines or cytokine receptor–like proteins that can modulate the immune response.15 Selective deletion of virus-specific CTLs due to immune exhaustion has been suggested in lymphocytic choriomeningitis virus (LCMV).16 Finally, the emergence of variants that escape antibody and CTL response have been described for HIV, hepatitis B virus (HBV), LCMV,17–19 as well as in HCV, as discussed below.
Potential Mechanisms of HCV Persistence The precise mechanism of HCV persistence despite apparent immune response is not well understood currently. HCV has not been shown to infect immunologically privileged sites. Extrahepatic replication of HCV in peripheral blood lymphocytes based on the detection of negative-strand HCV RNA has been reported, although this remains controversial because of the technical prob-
ANDREW K. DIEHL
19. Jodal M, Lundgren O. Neural reflex modulation of intestinal epithelial transport. In: Gaginella TS, ed. Regulatory mechanisms in gastrointestinal function. Boca Raton, FL: CRC Press, 1995:99– 144. 20. Skok VI, Groisman SD, Melnitchenko LV, Gersanich VV, Gmiro VE. Selective pharmacological blockade of parasympathetic and enteric ganglia. J Auton Nerv Syst 1991;35:211–217. 21. Timar Peregrin A, Svensson M, Jodal M, Lundgren O. Calcium channels and intestinal fluid secretion: an experimental study in vivo in rats. Acta Physiol Scand 1997;160:371–378. 22. Timar Peregrin A, Ahlman H, Jodal M, Lundgren O. Effects of
GASTROENTEROLOGY Vol. 115, No. 4
calcium channel blockade on intestinal fluid secretion: sites of action. Acta Physiol Scand 1997;160:379–386. 23. Timar Peregrin A. Calcium channels, nerves and intestinal secretion (thesis). Go¨teborg University, 1998.
Address requests for reprints to: Ove Lundgren, M.D., Ph.D., Department of Physiology, Go ¨teborg University, Box 432, 405 30 Go ¨teborg, Sweden. e-mail:[email protected] r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
Gallstone Disease in Mestizo Hispanics See article on page 937.
allstone disease is remarkably common and is a major contributor to health care costs in the United States. Approximately one fourth of white women older than 50 are affected,1 and more than 700,000 cholecystectomies were performed in this country in 1995.2,3 The disease is not distributed equally across racial and ethnic groups. African Americans have rates half those of non-Hispanic whites. In contrast, Native Americans and certain American Hispanic populations are at high risk for gallstones and their complications.1 The extraordinary prevalence of gallstones in the Pima tribe of Arizona is well known. Almost 30 years ago, Sampliner et al.4 found that more than 70% of Pima women aged 25 and older had a history of cholecystectomy or abnormal cholecystographic findings. Subsequent investigators have reported high rates in other North American indigenous groups, including the Chippewas, Micmacs, and Cree-Ojibwas.5,6 Moreover, Native Americans living in Alaska, New Mexico, and Bolivia have high mortality from gallbladder cancer, a disease intimately linked to gallstones. That these high rates are observed in native peoples who differ markedly in local environment, culture, and diet argues for a common, genetically determined predisposition to stone formation.5 Certain Hispanic populations in the United States also appear to be at above average risk for gallbladder diseases. Preliminary data from the Third National Health and Nutrition Examination Survey document a higher prevalence of gallstones among Mexican Americans than non-Hispanic whites.7 This population-based epidemiological survey, which used real-time ultrasonography,
G
confirms earlier reports using less rigorous methods.5 Our own studies have found that the higher risk of clinically diagnosed gallstones in Mexican American women persists in analyses accounting for interethnic differences in age, body mass index, waist-to-hip ratio, parity, glucose intolerance, socioeconomic status, and dietary preferences.5,8,9 Mexican Americans have a correspondingly high mortality from gallbladder cancer compared with non-Hispanic whites.5,10 However, the risk is not uniform among U.S. Hispanic subgroups. The Hispanic Health and Nutrition Examination Survey (Hispanic HANES) found that Mexican Americans had an elevated risk for gallstone disease in comparison with Cuban Americans and mainland Puerto Ricans, even after adjustment for other relevant risk factors.11 Gallbladder cancer mortality in Mexican Americans is more than twice that of Cuban Americans and Puerto Ricans.10 Data on U.S. Hispanics of Central or South American origin are sparse but suggest rates of gallbladder disease only slightly less than those of Mexican Americans.10 Of note, gallstone prevalence in Spain is similar to that in other European countries.12 Why should gallstone disease be such a problem in some, but not other, Hispanic populations? The leading hypothesis is based on concepts of genetic admixture. Some U.S. Hispanic subgroups, most notably the Mexican Americans, are known to have a mestizo (mixed) genetic heritage. Modern Mexican Americans are the descendants of the Native Americans who originally populated Mexico and of the European conquistadores and immigrants who began arriving early in the sixteenth century. Recent investigations estimate that 30%–50% of the genetic stock of Mexican Americans derives from Native American sources.13 In contrast, Native American
October 1998
genes are believed to be less prevalent in Cuban Americans and Puerto Ricans, because of the rapid decimation of the indigenous populations of their islands of origin during the Spanish Conquest. If the admixture hypothesis is correct, one would expect to find a gradient in the prevalence of gallbladder disease, with mestizo Hispanics having a prevalence higher than that of non-Hispanic whites, but less than unadmixed Native Americans. There are several documented examples of such a gradient. In New Mexico, Morris et al.14 calculated mortality for noncancerous gallbladder disease for the mestizo Spanish American population. Using death certificate data, they found rates of 7.3 per 100,000 for Spanish American women vs. 2.7 for non-Hispanic whites and 16.6 for Native American women. For men, the corresponding rates were 4.1, 2.8, and 15.3 per 100,000. Rates of gallbladder cancer mortality in Spanish Americans similarly fell between those for Native Americans and non-Hispanic whites.14 In Bolivia, Rios-Dalenz et al.15 found mestizos to have a gallbladder cancer incidence higher than that of ‘‘whites’’ but less than that of Native Americans15; a more recent study from that country had similar findings.16 In this issue of GASTROENTEROLOGY, Miquel et al.17 provide additional data from Chile in support of the admixture hypothesis. Chileans have a very high prevalence of gallbladder disease, and Chile’s mortality rate from gallbladder cancer is among the highest in the world. In fact, gallbladder cancer has in recent years surpassed stomach, cervix, and breast cancer as the leading cause of cancer death in Chilean women.18 The factors underlying these high rates have yet to be elucidated. In an elegant epidemiological study, Miquel et al.17 reexamined the role genetic admixture plays in explaining variations in gallstone disease prevalence among ethnic subpopulations in Chile. Three groups were sampled. The largest was a middle-low socioeconomic group of mestizo Hispanics from an urban neighborhood in Santiago. The investigators also examined an isolated population of Mapuche Native Americans living on a small island in a lake in rural southern Chile. Finally, the investigators surveyed an entirely unrelated group of Chilean Maoris living on Easter Island in the Pacific Ocean. Subjects were asked about a history of cholecystectomy and underwent screening ultrasonography. In contrast to most previous studies, Native American genetic admixture was measured directly via ABO blood group distribution and determination of mitochondrial DNA polymorphisms.
EDITORIALS
1013
As expected, the prevalence of gallstones differed in the three populations, Mapuches having the highest rates and Maoris the lowest. Mapuches had significantly higher estimates of Amerindian genetic heritage than Hispanic mestizos, although a large majority of Hispanics were found to have some Amerindian genes. Maoris had no evidence of Amerindian admixture. Thus, the overall findings support the admixture hypothesis. However, subgroup data are not uniform or consistent. Only Mapuches aged 35 years and younger, especially women, had higher gallstone prevalences than mestizo Hispanics. There was no significant difference in prevalence between Mapuches and Hispanics of either sex after adjustment for age, body mass index, parity, and serum high-density lipoprotein cholesterol level. The prevalence of gallstones in Maoris was significantly lower than that of mestizo Hispanics only in persons older than 50 years. However, because the study had relatively low statistical power, true between-group differences may have gone undetected. In addition, the high degree of Amerindian admixture among the mestizo Hispanics may have limited the investigators’ ability to delineate differences in prevalence among age and sex subgroups. A few studies have attempted to relate the degree of Native American admixture to gallstone risk within a mestizo Hispanic population. A substudy of Mexican Americans from the Hispanic HANES found that Native American admixture (estimated by the highly polymorphic GM immunoglobulin antigen system) was unrelated to gallstone prevalence in either sex.19 Hanis et al.20 used a panel of blood group antigens and enzyme markers to characterize the degree of admixture in Mexican Americans. They found that among women younger than 45 years, greater levels of admixture were associated with a higher prevalence of clinical gallbladder disease. This relationship was not observed in men or older women.20 Mitchell et al.13 used three independent measures of admixture to characterize Mexican Americans participating in the San Antonio Heart Study. They found women with the highest admixture 1.4–1.8 times more likely to have clinically diagnosed gallbladder disease than those with the least admixture, although only one of the three ratios was statistically significant. No significant impact of admixture was observed in men.13 Together these findings provide meager support for the genetic admixture hypothesis, although differences within mestizo groups might be expected to be more difficult to show than those between mestizos and Native Americans. It is notable that, as observed in the study by Miquel et al., the most prominent effects of admixture were observed in younger women. One might conclude that in conditions
1014
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of multifactorial cause (like cholelithiasis), the impact of genetic factors is more evident in youth. Alternatively, genetic factors may interact with hormonal or other biological differences related to gender. Despite the uncertain implications of the admixture studies performed to date, it is clear that Native Americans and mestizo Hispanics have higher rates of gallbladder disease than non-Hispanic whites. Some have argued that the postulated genetic predisposition to cholethiasis in Native Americans is the consequence of evolutionary forces. According to this theory, the first persons to cross the Bering land bridge from Asia 10–20,000 years ago faced harsh environmental conditions, with unpredictable periods of nutritional and caloric insufficiency. Under these selection pressures, genes that promoted the efficient utilization and storage of nutrients by females might have become more prevalent. Such evolutionary drift of a ‘‘thrifty gene’’ might, eons later, result in the rapid formation of cholesterol gallstones under the conditions of nutritional plenty these populations are now experiencing.21,22 Stimulated by the discovery of the Lith1 gene in an inbred mouse model,23 investigators are now seeking a corresponding gene in humans. Currently, surprisingly little is known of the pathogenesis of gallstone formation in Native Americans and mestizo Hispanics. It has been established that Pimas rapidly develop lithogenic bile at puberty.24 However, Mexican Americans are no more likely to present with cholesterol or mixed composition stones than nonHispanic whites, and stones recovered at surgery from the two groups are remarkably similar in size and number.25 Future studies should examine other aspects of stone pathogenesis in Native American and admixed populations including gallbladder emptying, which has been found to differ between racial groups.26 Given the magnitude of gallbladder disease prevalence and the resources currently devoted to its treatment, our goal should be to develop a practical means to prevent stone formation. Insights will come from basic science as well as epidemiological studies. Further exploration of the mechanisms underlying the high prevalence of gallstone disease in Native Americans and mestizo Hispanics may be especially fruitful. ANDREW K. DIEHL Division of General Medicine Department of Medicine University of Texas Health Science Center San Antonio, Texas
References 1. Diehl AK. Epidemiology and natural history of gallstone disease. Gastroenterol Clin North Am 1991;20:1–19.
GASTROENTEROLOGY Vol. 115, No. 4
2. Graves EJ, Owings MF. 1995 summary: National Hospital Discharge Survey. Advance data from vital and health statistics; no. 291. Hyattsville, MD: National Center for Health Statistics, 1997. 3. Hall MJ, Lawrence L. Ambulatory surgery in the United States, 1995. Advance data from vital and health statistics; no. 296. Hyattsville, MD: National Center for Health Statistics, 1997. 4. Sampliner RE, Bennett PH, Comess LJ, Rose FA, Burch TA. Gallbladder disease in Pima Indians. Demonstration of high prevalence and early onset by cholecystography. N Engl J Med 1970;283:1358–1364. 5. Diehl AK, Stern MP. Special health problems of MexicanAmericans: obesity, gallbladder disease, diabetes mellitus, and cardiovascular disease. Adv Intern Med 1989;34:73–96. 6. Young TK, Roche BA. Factors associated with clinical gallbladder disease in a Canadian Indian population. Clin Invest Med 1990; 13:55–59. 7. Khare M, Everhart JE, Maurer KR, Hill MC. Prevalence of gallstone disease in the United States (abstr). Hepatology 1994;20:118A. 8. Haffner SM, Diehl AK, Mitchell BD, Stern MP, Hazuda HP. Increased prevalence of clinical gallbladder disease in subjects with non–insulin-dependent diabetes mellitus. Am J Epidemiol 1990;132:327–335. 9. Diehl AK, Haffner SM, Knapp JA, Hazuda HP, Stern MP. Dietary intake and the prevalence of gallbladder disease in Mexican Americans. Gastroenterology 1989;97:1527–1533. 10. Wagener DK, McDonald M. Increased gallbladder-related mortality among Hispanics: does education play a role? Ethn Health 1996;1:197–205. 11. Maurer KR, Everhart JE, Knowler WC, Shawker TH, Roth HP. Risk factors for gallstone disease in the Hispanic population of the United States. Am J Epidemiol 1990;131:836–844. 12. Martinez de Pancorbo C, Carballo F, Horcajo P, Aldeguer M, Hazuda HP, Haffner SM, Stern MP. Prevalence and associated factors for gallstone disease: results of a population survey in Spain. J Clin Epidemiol 1997;50:1347–1355. 13. Mitchell BD, Williams-Blangero S, Chakraborty R, Valdez R, de la Villa I, Nieto E, Gaspar MJ, de la Moreno J. A comparison of three methods for assessing Amerindian admixture in Mexican Americans. Ethn Dis 1993;3:22–31. 14. Morris DL, Buechley RW, Key CR, Morgan MV. Gallbladder disease and gallbladder cancer among American Indians in tricultural New Mexico. Cancer 1978;42:2472–2477. 15. Rios-Dalenz J, Takabayashi A, Henson DE, Strom BL, Soloway RD. The epidemiology of cancer of the extra-hepatic biliary tract in Bolivia. Int J Epidemiol 1983;12:156–180. 16. Strom BL, Soloway RD, Rios-Dalenz J, Rodriguez-Martinez HA, West SL, Kinman JL, Polansky M, Berlin JA. Risk factors for gallbladder cancer. An international collaborative case-control study. Cancer 1995;76:1747–1756. 17. Miquel JF, Covarrubias C, Villaroel L, Mingrone G, Greco AV, Puglielli L, Carvallo P, Marshall G, Del Pino G, Nervi F. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris. Gastroenterology 1998;115:937– 946. 18. Serra I, Calvo A, Maturana M, Sharp A. Biliary-tract cancer in Chile. Int J Cancer 1990;46:965–971. 19. Everhart JE, Knowler WC, Maurer KR, Harris MI, Schanfield MS, Go VLW. Does American Indian admixture contribute to obesity, diabetes, and gallbladder disease among Mexican Americans? Am J Epidemiol 1989;130:840. 20. Hanis CL, Chakraborty R, Ferrell RE, Schull WJ. Individual admixture estimates: disease associations and individual risk of diabetes and gallbladder disease among Mexican-Americans in Starr County, Texas. Am J Phys Anthropol 1986;70:433–441. 21. Weiss KM, Ferrell RE, Hanis CL, Styne PN. Genetics and epidemiology of gallbladder disease in New World native peoples. Am J Hum Genet 1984;36:1259–1278.
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EDITORIALS
22. Lowenfels AB. Gallstones and glaciers: the stone that came in from the cold. Lancet 1988;1:1385–86. 23. Khanuja B, Cheah Y-C, Hunt M, Nishina PM, Wang DQ-H, Chen HW, Billheimer JT, Carey MC, Paigen B. Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc Natl Acad Sci 1995;92:7729–7733. 24. Bennion LJ, Knowler WC, Mott DM, Spagnola AM, Bennett PM. Development of lithogenic bile during puberty in Pima Indians. N Engl J Med 1979;300:873–876. 25. Diehl AK, Schwesinger WH, Holleman DR Jr, Chapman JB, Kurtin WE. Gallstone characteristics in Mexican Americans and nonHispanic whites. Dig Dis Sci 1994;39:2223–2228.
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26. Davion T, Tossou H, Delamarre J, Capron J-P. Racial differences in gallbladder motor function. Lancet 1989;1:724–725.
Address requests for reprints to: Andrew K. Diehl, M.D., Division of General Medicine, Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7879. e-mail: [email protected]; fax: (210) 223-6166. r 1998 by the American Gastroenterological Association 0016-5085/98/$3.00
The Mechanisms of Chronicity in Hepatitis C Virus Infection See article on page 954.
he outcome of a viral infection is defined by the interplay between the virus and host immune response. Clearance of a virus is usually associated with a vigorous antiviral T-cell response. Because viruses are intracellular pathogens, CD8 cytotoxic T lymphocytes (CTLs) that can directly kill infected cells and produce potent antiviral cytokines are thought to be crucial in viral eradication and disease control. In contrast, persistent viruses are relatively noncytopathic viruses that successfully evade immune detection and elimination. Indeed, the latter are very sophisticated viruses that have developed various mechanisms to subvert or obfuscate the host immune system to survive. Hepatitis C virus (HCV) is particularly interesting in this context because of its high rate of chronicity (.70%).1 Since its identification and molecular characterization in 1989,2 this hepatotropic positive-stranded RNA virus has emerged as an important pathogen that infects more than 1% of the world population.3,4 Paradoxically, chronic hepatitis C occurs in the face of a readily detectable multispecific humoral and cellular immune response directed against all of the viral structural and nonstructural proteins.5–7 Because persistent HCV infection is usually associated with chronic hepatitis, which often progresses to cirrhosis, and may lead to hepatocellular carcinoma, considerable interest has been focused on potential mechanisms of viral persistence and immune evasion.8–11 In this editorial, potential mechanisms of HCV persistence, including the role of CTL escape, are discussed in the context of published literature and the current article by Tsai et al.12 in this issue of GASTROENTEROLOGY.
T
Proposed Mechanisms of Viral Immune Evasion The host defense mechanisms against viral pathogens include innate responses such as natural killer cells and interferons that are antigen-nonspecific and antigenspecific immune responses such as antibody, CD4, and CD8 T-cell response. In this context, viruses can persist by interfering with components of the immune response. They can compromise the immune system directly by infecting lymphocytes and antigen-presenting cells, as evident in human immunodeficiency virus (HIV) infection.13 They can avoid immune recognition by infecting immunologically privileged sites or by remaining latent, as shown by herpes simplex virus. Viruses such as adenoviruses, HIV, and herpesviruses have been shown to interfere with antigen processing,14 whereas Epstein– Barr virus, poxvirus, and others produce viral cytokines or cytokine receptor–like proteins that can modulate the immune response.15 Selective deletion of virus-specific CTLs due to immune exhaustion has been suggested in lymphocytic choriomeningitis virus (LCMV).16 Finally, the emergence of variants that escape antibody and CTL response have been described for HIV, hepatitis B virus (HBV), LCMV,17–19 as well as in HCV, as discussed below.
Potential Mechanisms of HCV Persistence The precise mechanism of HCV persistence despite apparent immune response is not well understood currently. HCV has not been shown to infect immunologically privileged sites. Extrahepatic replication of HCV in peripheral blood lymphocytes based on the detection of negative-strand HCV RNA has been reported, although this remains controversial because of the technical prob-